Regulación de sistema ubiquitina-proteasoma por los receptores purinérgicos en el sistema nervioso central

Los nucleótidos, que se comportan como neurotransmisores en el SNC, se encuentran implicados en una gran variedad de procesos fisiológicos y patológicos (Bodin & Burnstock 2001). Este papel como neurotransmisores se debe a que pueden activar diferentes receptores específicos de la membrana celular, denominados receptores purinérgicos P2 (Burnstock 2007). Estos receptores se dividen en dos grupos: receptores ionotrópicos (P2X1-7) y receptores metabotrópicos (P2Y1,2,4,6,11-14) (Burnstock et al 2012). Los receptores metabotrópicos P2Y se expresan en los diferentes linajes celulares del SNC donde regulan una gran variedad de procesos fisiológicos como la proliferación, crecimiento o supervivencia celular (Khakh & Burnstock 2009). Dentro de los receptores P2Y, el receptor P2Y2 posee unas características estructurales especiales que le permiten interaccionar tanto con integrinas como con otros receptores, lo cual hace que esté implicado en numerosos fenómenos fisiológicos y patológicos (Weisman et al 2012). De hecho, se ha postulado que el receptor P2Y2 representa una prometedora diana terapéutica para el tratamiento de algunas enfermedades. El papel neuroprotector asociado a dicho receptor ha sido observado principalmente bajo condiciones de neuroinflamación, estrés oxidativo y en enfermedades neurodegenerativas (Weisman et al 2012). Normalmente, estas situaciones se encuentran asociadas a un aumento de la cantidad de proteínas mal plegadas en el interior celular, hecho relacionado a su vez con un mal funcionamiento del Sistema Ubiquitina-Proteasoma (UPS) (Dantuma & Lindsten 2010). El UPS es el principal sistema encargado de controlar la proteostasis celular (Kaushik & Cuervo 2015), degradando de una manera específica y selectiva la mayoría de las proteínas intracelulares. Mediante la acción coordinada de las enzimas E1, E2 y E3, la proteína a degradar será marcada con una cadena de moléculas de Ubiquitina para posteriormente ser degradada por el proteasoma (Hershko & Ciechanover 1998)..

Reliability ofwood utility poles under stochastic wind load and material considering knots

Wood utility poles are simple structures used in power networks and their failure may produce a significant impact on their reliability as well as economic consequences. Wind loads are one of the main causes of damage in wood utility poles. The present study addresses the dynamic behavior of Argentinean Eucalyptus grandis wood poles with uncertain material properties under stochastic wind load. Regarding the material, the lengthwise variability of the Modulus of Elasticity (MOE) and the second moment of area are simulated through the Weak Zone (WZ) model taking into account the knots presence. The stochastic wind velocity field is derived using the Spectral Representation Method (SRM) considering temporal and spatial correlation. Then, the wind load is obtained under the considerations of the Argentinean standard CIRSOC 102. The governing equations are discretized through the Finite Element Method (FEM). The stochastic analysis is performed by means of Monte Carlo Simulations (MCS). In this study, displacements are evaluated such that a percentage of damage is found for each wind velocity. Fragility curves are a useful means to evaluate the failure probability of the poles for a defined failure mode, under a given range of demand, here the wind load. The WZ model results are compared with other MOE models previously developed (as a random variable and as a random field through the Non Gaussian Karhunen-Loève Expansion). Also, confidence bands of the fragility curves are obtained for 95% of confidence.Publicado en: Mecánica Computacional vol. XXXV, no. 21Facultad de Ingenierí

Reliability ofwood utility poles under stochastic wind load and material considering knots

Wood utility poles are simple structures used in power networks and their failure may produce a significant impact on their reliability as well as economic consequences. Wind loads are one of the main causes of damage in wood utility poles. The present study addresses the dynamic behavior of Argentinean Eucalyptus grandis wood poles with uncertain material properties under stochastic wind load. Regarding the material, the lengthwise variability of the Modulus of Elasticity (MOE) and the second moment of area are simulated through the Weak Zone (WZ) model taking into account the knots presence. The stochastic wind velocity field is derived using the Spectral Representation Method (SRM) considering temporal and spatial correlation. Then, the wind load is obtained under the considerations of the Argentinean standard CIRSOC 102. The governing equations are discretized through the Finite Element Method (FEM). The stochastic analysis is performed by means of Monte Carlo Simulations (MCS). In this study, displacements are evaluated such that a percentage of damage is found for each wind velocity. Fragility curves are a useful means to evaluate the failure probability of the poles for a defined failure mode, under a given range of demand, here the wind load. The WZ model results are compared with other MOE models previously developed (as a random variable and as a random field through the Non Gaussian Karhunen-Loève Expansion). Also, confidence bands of the fragility curves are obtained for 95% of confidence.Publicado en: Mecánica Computacional vol. XXXV, no. 21Facultad de Ingenierí

Reliability ofwood utility poles under stochastic wind load and material considering knots

Wood utility poles are simple structures used in power networks and their failure may produce a significant impact on their reliability as well as economic consequences. Wind loads are one of the main causes of damage in wood utility poles. The present study addresses the dynamic behavior of Argentinean Eucalyptus grandis wood poles with uncertain material properties under stochastic wind load. Regarding the material, the lengthwise variability of the Modulus of Elasticity (MOE) and the second moment of area are simulated through the Weak Zone (WZ) model taking into account the knots presence. The stochastic wind velocity field is derived using the Spectral Representation Method (SRM) considering temporal and spatial correlation. Then, the wind load is obtained under the considerations of the Argentinean standard CIRSOC 102. The governing equations are discretized through the Finite Element Method (FEM). The stochastic analysis is performed by means of Monte Carlo Simulations (MCS). In this study, displacements are evaluated such that a percentage of damage is found for each wind velocity. Fragility curves are a useful means to evaluate the failure probability of the poles for a defined failure mode, under a given range of demand, here the wind load. The WZ model results are compared with other MOE models previously developed (as a random variable and as a random field through the Non Gaussian Karhunen-Loève Expansion). Also, confidence bands of the fragility curves are obtained for 95% of confidence.Publicado en: Mecánica Computacional vol. XXXV, no. 21Facultad de Ingenierí

University TV through Internet: Analysis of the Spanish Situation

Con Internet la televisión se ha transformado en diferentes direcciones: su acceso a través de distintos dispositivos, su convergencia con tecnologías de la web 2.0 y los “social media”. Tal unificación ha traído la denominada TVIP o bajo streaming, en la cual las Universidades han desarrollados diferentes canales. En el artículo se analizan las TVIP de Universidades españolas, efectuándose para ello un análisis de contenido. Se concluye que el medio está adquiriendo progresiva importancia, y se presentan sus características y servicios que ofrecen. Se apuntan también algunas limitaciones de estas cadenas.Internet television has transformed in different directions: access via different devices, its convergence with web 2.0 technologies and "social media". Such unification brought under the so-called IPTV or streaming, in which the universities have developed different channels. In the article the IPTV Spanish Universities are analyzed effected to do a content analysis. We conclude that the medium is gaining increasing importance, and its features and services offered are presented. Some limitations of these chains are also targeted

Integrin Linked Kinase (ILK) Downregulation as an Early Event During the Development of Metabolic Alterations in a Short-Term High Fat Diet Mice Model.

Background/Aims: Diabetes type 2, metabolic syndrome or non-alcoholic fatty liver disease are insulin resistance-related metabolic disorders, which lack a better prognosis before their full establishment. We studied the importance of the intracellular scaffold protein integrin linked kinaes (ILK) as a key modulator in the initial pathogenesis and the early progression of those insulin resistance- related disorders. Methods: Adult mice with a global transgenic downregulation of ILK expression (cKD-ILK) and littermates without that depletion (CT) were fed with either standard (STD) or high fat (HFD) diets during 2 and 6 weeks. Weights, blood glucose and other systemic biochemical parameters were determined in animals under fasting conditions and after glucose or pyruvate intraperitoneal injections to test their tolerance. In RNA or proteins extracted from insulin-sensitive tissues, we determined by reverse transcription?quantitative PCR and western blot the expression of ILK, metabolites transporters and other metabolism and inflammatory markers. Glucose uptake capacity was studied in freshly isolated tissues. Results: HFD feeding was able to early and progressively increase glycaemia, insulinemia, circulating glycerol, body weight gain, liver-mediated gluconeogenesis along this time lapse, but cKD-ILK have all these systemic misbalances exacerbated compared to CT in the same HFD time lapse. Interestingly, the tisular expression of ILK in HFD-fed CT was dramatically downregulated in white adipose tissue (WAT), skeletal muscle and liver at the same extent of the original ILK downregulation of cKD-ILK. We previously published that basal STD-fed cKD-ILK compared to basal STD-CT have different expression of glucose transporters GLUT4 in WAT and skeletal muscle. In the same STD-fed cKD-ILK, we observed here the increased expressions of hepatic GLUT2 and WAT pro-inflammatory cytokines TNF-? and MCP-1. The administration of HFD exacerbated the expression changes in cKD-ILK of these and other markers related to the imbalanced metabolism observed, such as WAT lipolysis (HSL), hepatic gluconeogenesis (PCK-1) and glycerol transport (AQP9). Conclusion: ILK expression may be taken as a predictive determinant of metabolic disorders establishment, because its downregulation seems to correlate with the early imbalance of glucose and glycerol transport and the subsequent loss of systemic homeostasis of these metabolites.Instituto de Salud Carlos III-ISCIIIComunidad de MadridFondo Europeo de Desarrollo Regional-FEDERInstituto Ramon y Cajal de Investigación Sanitária-IRYCISFundación Renal Iñigo Álvarez de Toledo-FRIA

The Integrin Beta1 Modulator Tirofiban Prevents Adipogenesis and Obesity by the Overexpression of Integrin-Linked Kinase: a Pre-Clinical Approach In Vitro and In Vivo

de Frutos, S., Griera, M., Hatem-Vaquero, M. et al. The integrin beta1 modulator Tirofiban prevents adipogenesis and obesity by the overexpression of integrin-linked kinase: a pre-clinical approach in vitro and in vivo. Cell Biosci 12, 10 (2022)Background: Obesity is caused by the enlargement of the white adipose tissue (WAT) depots, characterized by the hypertrophic enlargement of malfunctioning adipocytes within WAT which increases the storage of triglycerides (TG) in the lipid droplets (LD). Adipogenesis pathways as well as the expression and activity of some extracellular matrix receptors integrins are upregulated. Integrin?1 (INTB1) is the main isoform involved in WAT remodeling during obesity and insulin resistance-related diseases. We recently described Integrin Linked Kinase (ILK), a scafold protein recruited by INTB1, as an important mediator of WAT remodeling and insulin resistance. As the few approved drugs to fght obesity have brought long-term cardiovascular side efects and given that the consideration of INTB1 and/or ILK modulation as anti-obesogenic strategies remains unexplored, we aimed to evaluate the anti-obesogenic capacity of the clinically approved anticoagulant Tirofban (TF), stated in preclinical studies as a cardiovascular protector. Methods: Fully diferentiated adipocytes originating from C3H10T1/2 were exposed to TF and were co-treated with specifc INTB1 blockers or with siRNA-based knockdown ILK expression. Lipid-specifc dyes were used to determine the TG content in LD. The genetic expression pattern of ILK, pro-infammatory cytokines (MCP1, IL6), adipogenesis (PPAR?, Leptin), thermogenesis (UCP1), proliferation (PCNA), lipid metabolism (FASN, HSL, ATGL), and metabolite trans porters (FABP4, FAT, AQP7) were detected using quantitative PCR. Cytoskeletal actin polymerization was detected by confocal microscopy. Immunoblotting was performed to detect INTB1 phosphorylation at Thr788/9 and ILK activity as phosphorylation levels of protein kinase B (AKT) in Ser473 and glycogen synthase kinase 3? (GSK3?) at Ser9. TF was intraperitoneally administered once per day to wildtype and ILK knockdown mice (cKDILK) challenged with a high-fat diet (HFD) or control diet (STD) for 2 weeks. Body and WAT weight gains were compared. The expression of ILK and other markers was determined in the visceral epididymal (epi) and inguinal subcutaneous (sc) WAT. Results: TF reduced TG content and the expression of adipogenesis markers and transporters in adipocytes, while UCP-1 expression was increased and the expression of lipases, cytokines or PCNA was not afected. Mechanistically, TF rapidly increased and faded the intracellular phosphorylation of INTB1 but not AKT or GSK3?. F-actin levels were rapidly decreased, and INTB1 blockade avoided the TF efect. After 24 h, ILK expression and phosphorylation rates of AKT and GSK3? were upregulated, while ILK silencing increased TG content. INTB1 blockade and ILK silencing avoided TF efects on the TG content and the transcriptional expression of PPAR? and UCP1. In HFD-challenged mice, the systemic administration of TF for several days reduced the weight gain on WAT depots. TF reduced adipogenesis and pro-infammatory biomarkers and increased lipolysis markers HSL and FAT in epiWAT from HFD, while increased UCP1 in scWAT. In both WATs, TF upregulated ILK expression and activity, while no changes were observed in other tissues. In HFD-fed cKDILK, the blunted ILK in epiWAT worsened weight gain and avoided the anti-obesogenic efect of in vivo TF administration. Conclusions: ILK downregulation in WAT can be considered a biomarker of obesity establishment. Via an INTB1-ILK axis, TF restores malfunctioning hypertrophied WAT by changing the expression of adipocyte-related genes, increas ing ILK expression and activity, and reducing TG storage. TF prevents obesity, a property to be added to its anticoagu lant and cardiovascular protective advantages.Instituto de Salud Carlos IIIComunidad de MadridFondo Europeo de Desarrollo Regional-FEDE

La televisión universitaria por Internet: análisis de la situación española

Con Internet la televisión se ha transformado en diferentes direcciones: su acceso a través de distintos dispositivos, su convergencia con tecnologías de la web 2.0 y los “social media”. Tal unificación ha traído la denominada TVIP o bajo streaming, en la cual las Universidades han desarrollados diferentes canales. En el artículo se analizan las TVIP de Universidades españolas, efectuándose para ello un análisis de contenido. Se concluye que el medio está adquiriendo progresiva importancia, y se presentan sus características y servicios que ofrecen. Se apuntan también algunas limitaciones de estas cadenas

Physical performance and quality of life in older adults: Is there any association between them and potential drug interactions in Polymedicated Octogenarians?

Producción CientíficaOlder adults are at increased risk of several cytochrome P450 (CYP) drug interactions that can result in drug toxicity, reduced pharmacological effect, and adverse drug reactions. This study aimed to assess the prevalence of potential CYP interactions referring to the most clinically relevant drugs and exploring the relationship between them and quality of life and physical performance in Spanish octogenarians. Institutionalized and community-dwelling octogenarians (n = 102) treated at three primary care centers, were recruited by a research nurse. Anthropometric measurements, chronic diseases, prescribed drugs, quality of life, physical performance, mobility skills, hand grip strength and cognitive status data were collected. Potential CYP drug-drug interactions (DDIs) were selected referring to the main CYP implicated in their metabolism. The 72.2% of recruited octogenarians presented potentially inappropriate CYP inhibitor-substrate or CYP inductor-substrate combinations. Analyzing the EuroQol Visual Analogue scale (EQ-VAS) results, patients with a potential CYP DDI perceived worse health status than patients without it (p = 0.004). In addition, patients with a potential CYP DDI presented worse exercise capacity, kinesthetic abilities, or mobility than those who didn’t present a potential interaction (p = 0.01, p = 0.047, and p = 0.02, respectively). To investigate and control factors associated with loss of muscle strength and poor quality of life, polypharmacy and DDIs could help institutions in the management of physical frailty.Fundación Científica Caja Rural de Soria (project 00200200227

Recycled polyethylene fibres for structural concrete

Modern society demands more sustainable and economical construction elements. One of the available options for manufacturing this type of element is the valorisation of end-of-life waste, such as, for example, the recycling of polymers used in industry. The valorisation of these wastes reduces costs and avoids the pollution generated by their landfill disposal. With the aim of helping to obtain this type of material, this work describes a methodology for recycling polyethylene for the manufacture of fibres that will later be used as reinforcement for structural concrete. These fibres are manufactured using an injection moulding machine. Subsequently, their physical and mechanical properties are measured and compared with those of the material before it is crushed and injected. The aim of this comparison is to evaluate the recycling process and analyse the reduction of the physical-mechanical properties of the recycled polyethylene in the process. Finally, to determine the properties of the fibre concrete, three types of concrete were produced: a control concrete, a reinforced concrete with 2 kg/m³ of fibres, and a reinforced concrete with 4 kg/m³ of fibres. The results show an enhancement of mechanical properties when the fibres are incorporated, particularly the tensile strength; and they also show excellent performance controlling cracking in concrete.This research was funded by the LADICIM (Laboratory of Materials Science and Engineering), Universidad de Cantabria. E.T.S. de Ingenieros de Caminos, Canales y Puertos, Av./Los Castros 44, 39005 Santander, Spain